ORGANIC LETTERS
Efficient and Z-Selective Cross-Metathesis of Conjugated Enynes
2004 Vol. 6, No. 12 2035-2038
Eric C. Hansen and Daesung Lee* Department of Chemistry, UniVersity of WisconsinsMadison, Madison, Wisconsin 53706
[email protected] Received April 6, 2004
ABSTRACT
The generation of a conjugated alkynyl alkylidene has been achieved using an allyl ether moiety as an intramolecular catalyst delivery vehicle. The reaction of this intermediate with alkenes and alkynes yields conjugated enynes with Z-selectivity.
Olefin metathesis has become a powerful carbon-carbon bond-forming method which has had a profound impact in synthetic chemistry.1 The extensive research involving olefin metathesis is driven by the development of well-defined reactive ruthenium2 and molybdenum-based catalysts3 showing broad functional group compatibility. From the standpoint of new applications of metathesis chemistry, the synthesis of enediynes via the metathesis process is an attractive yet challenging goal (eq 1). The enediyne substructure constitutes (1) For reviews on olefin metathesis, see: (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413. (b) Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371. (c) Blechert, S. Pure Appl. Chem. 1999, 71, 1393. (d) Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3013. (e) Connon, S. J.; Blechert, S. Angew. Chem., Int. Ed. 2003, 42, 1900. (f) Schrock, R. R.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2003, 42, 4592. For recent reviews of enyne metathesis, see: (g) Giessert, A. J.; Diver, S. T. Chem. ReV. 2004, 104, 1317. (h) Poulsen, C. S.; Madsen, R. Synthesis 2003, 1. (i) Mori, M. Top. Organomet. Chem. 1998, 1, 133. (2) (a) Nguyen, S. T.; Johnson, L. K.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1992, 114, 3974. (b) Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28, 446. (c) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996, 118, 100. (d) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953. (e) Scholl, M.; Trnka, T. M.; Morgan, J. P.; Grubbs, R. H. Tetrahedron Lett. 1999, 40, 2247. (f) Huang, J.; Stevens, E. D.; Nolan, S. P.; Peterson, J. L. J. Am. Chem. Soc. 1999, 121, 2674. (3) (a) Schrock, R. R.; Murdzek, J. S.; Bazan, G. C.; Robbins, J.; Dimare, M.; O’Reagan, M.; Thomas, J. K.; Davis, W. M. J. Am. Chem. Soc. 1990, 112, 3875. (b) Bazan, G. C.; Oskam, J. H.; Cho, H.-N.; Park, L. Y.; Schrock, R. R. J. Am. Chem. Soc. 1991, 113, 6899. 10.1021/ol049378i CCC: $27.50 Published on Web 05/19/2004
© 2004 American Chemical Society
the unique architecture of the enediyne family of natural products that are characterized by their potent antitumor and antibiotic activities.4 Typically, the enediyne functionality is embedded in either a nine-membered ring 1 (bicyclo[7.3.0]dodecadiynene) or a 10-membered ring 2 (bicyclo[7.3.1]tridecadiynene) as a stable precursor, which upon activation leads to benzene-1,4-diyl. It has been shown that the diyl generated by the Bergman-5 or Myers-type cycloaromatization6 of enediyne warheads induces single and double strand DNA cleavage, which is presumed to be the basis for the potent in vitro and in vivo biological activity. Both the novel structural and biological characteristics of the enediynes have invited intense synthetic as well as clinical studies.7 Numerous synthetic methods have been developed to construct the enediyne substructures, and many total syntheses of complex natural enediynes have been reported.4 (4) For reviews on enediynes, see: (a) Grissom, J. W.; Gunawardena, G. U.; Klingberg, D.; Huang, D. Tetrahedron 1996, 52, 6453. (b) Maier, M. E. Synlett 1995, 13. (c) Nicolaou, K. C.; Dai, W.-M. Angew. Chem., Int. Ed. 1991, 30, 1387. (5) Bergman, R. G. Acc. Chem. Res. 1973, 6, 25. (6) Myers, A. G. Tetrahedron Lett. 1987, 28, 4493. (7) For overview of recent clinical findings, see: (a) Schor, N. F. In Cancer Therapeutics: Experimental and Clinical Agents; Teicher, B., Ed.; Humana Press: Totowa, NJ, 1996; p 229. (b) Maeda, H.; Edo, K.; Ishida, N. Eds., Neocarzinostatin: The Past, Present, and Future of an Anticancer Drug; Springer-Verlag: New York, 1997.
Table 1. Diene CM Reaction of Terminal Conjugated Enynesa
However, to the best of our knowledge, no attempt to synthesize enediynes and related structures using metathesis chemistry has been reported. We were intrigued by the possibility of constructing the enediyne substructure directly from conjugated enyne precursors via cross-metathesis (CM).1e For this plan to be viable, the efficient generation of conjugated alkynyl alkylidene 4 is crucial and its reactivity toward both alkene and alkyne substrates needs to be understood.8 There are several reports that describe the use of conjugated and unconjugated enynes as CM counterparts either in the presence of catalyst 6 or a more active version 7,9 yet the CM reaction involving the
Figure 1.
conjugated alkynyl alkylidene of type 4 as a propagating species has not been reported.10 We developed an efficient way of generating alkylidene 4 from precursor 5 that carries a more active terminal alkene appendage as a catalyst delivery vehicle. Herein we wish to report the first successful generation of conjugated alkynyl alkylidene 4 and its use in the context of CM reaction. To calibrate the reactivity of simple conjugated enynes toward the CM reaction similar to those reported by Chang and co-workers,9 the CM reaction of enynes 3a,b and several alkene counterparts were examined (Table 1). Quite unexpectedly, enynes 3a,b are reasonably good substrates for CM (8) (a) Trnka, T. M.; Day, M. W.; Grubbs, R. H. Organometallics 2001, 20, 3845. (b) von Otterlo, W. A. L.; Ngidi, E. L.; de Knoing, C. B.; Fernandes, M. A. Tetrahedron Lett. 2004, 45, 659. (9) (a) Kang, B.; Kim, D.-h.; Do, Y.; Chang, S. Org. Lett. 2003, 5, 3041. (b) Ratnayake, A. S.; Hemscheidt, T. Org. Lett. 2002, 4, 4667. (10) Mechanistically, conjugated alkenyl alkylidenes are involved in all enyne methathesis processes. For recent examples of ring closing metathesis reactions employing conjugated dienes as starting materials to generate the putative conjugated alkenyl alkylidenes as intermediates, see: (a) Frederique, R.; Claire, V.; Laurent, E.; Laurence, G. Org. Lett. 2003, 5, 2007. (b) Wang, X.; Porco, J. A., Jr. J. Am. Chem. Soc. 2003, 125, 6040. (c) Evano, G.; Schaus, J. V.; Panek, J. S. Org. Lett. 2004, 6, 525. 2036
a Catalyst 6 (5-10 mol %) was added to a solution of the enyne and the alkene in CH2Cl2. b Determined by 1H NMR. c Isolated yield.
reaction with catalyst 6. First, substrate 3a containing a terminal enyne conjugated to a carbonyl group was reacted with symmetric disubstituted cis-alkene 8a affording a moderate yield (34%) of the cross-coupled product 9a as 1:7 mixture of E/Z isomers (entry 1). The related enyne 3b possessing an acetate instead of the carbonyl group at the propargylic site reacted with 8a to afford the expected CM product 9b in 37% yield with a significantly increased E/Z ratio of 1:20 (entry 2).9,11,12 The CM reaction between 3b and trimethylallylsilane 8b yielded the cross-coupled product in 40% yield with a 1:5 ratio of E/Z isomers (entry 3). In terms of overall reactivity, the electron-deficient substrate 3a seems to be less reactive compared to 3b, taking much longer reaction time to reach similar conversion (18 h vs 8 h). The successful examples of CM reactions in Table 1 are in sharp contrast to those reported by Chang in which the CM reactions of conjugated enynes failed by using 6, requiring the use of more active catalyst 7. Thus, the catalyst deactivation by the putative complexation between catalyst and simple conjugated enynes suggested by these authors is not the major encumbrance for the metathesis of conjugated enynes 3a,b, which is probably the consequence of different stereoelectronic environments caused by dissimilar substituents on the alkyne. The CM with more active catalyst 7 afforded 9a in slightly improved yield (45% vs 34%) but overall performance of 7 was quite similar to that of 6. Mechanistically, we believe that the catalytic cycle of this enyne-alkene CM reaction starts from the reaction between alkenes 8a-c and catalyst 6 (the top half of Scheme 1). The resultant propagating alkylidene species 10 then reacts with conjugated alkyne 3a,b, generating metalacyclobutane 11, the [2 +2] cycloreversion of which gives a CM product 9a-c and methylidene, which initiates another round of the catalytic cycle. The moderate yields obtained in Table 1 are probably the consequence of the low reactivity of conjugated enynes 3a,b toward the propagating alkylidene 10. Due to the lack of flexibility in modulating the reactivity of simple enynes 3a,b, we considered the development of a new type of enyne substrate 5 that would participate in metathesis reactions with completely different reaction Org. Lett., Vol. 6, No. 12, 2004
Scheme 1.
Two Different Catalytic Cycles for the CM Reaction
manifold (the bottom half of Scheme 2). For substrate 5, with the allyl ether appendage acting as a catalyst delivery vehicle, the CM reaction will selectively initiate at the terminal olefin of the allyl group, generating the conjugated alkynyl alkylidene 4 after the extrusion of dihydrofuran.13 Subsequent reaction of the alkylidene 4 with alkene 8 to form the metalacyclobutane intermediate 12 followed by its cycloreversion would provide CM products 14. Overall, the biggest difference between these two catalytic cycles is the step forming 11 and 12. We believe that the reaction of alkylidene 10 and conjugated enyne 3a,b is slower than that of conjugated alkylidene 4 and alkene 8, thereby providing lower overall CM efficiency.14 On the basis of this mechanistic hypothesis, we prepared substrates 5a-e that contain the allyl ether moiety and carried out their CM reactions.15 With the more active conjugated enyne equivalent 5a-e, the CM product 9a and 14a-e were obtained in significantly improved chemical yields yet with somewhat decreased E/Z selectivity for certain substrates (Table 2). The CM reaction of 5a with alkene 8a afforded (11) Love, J. A.; Morgan, J. P.; Trnka, T. M.; Grubbs, R. H. Angew. Chem., Int. Ed. 2002, 41, 4035. (12) The Z-selective cross metathesis of acrylonitrile, see: (a) Crowe, W. E.; Goldberg D. R. J. Am. Chem. Soc. 1995, 117, 5162. (b) Randle, S.; Gessler, S.; Wakamatsu, H.; Blechert, S. Synlett 2001, 430. Org. Lett., Vol. 6, No. 12, 2004
Scheme 2
improved yield of 9a within shorter reaction time (entry 1 in Table 2; 6 h, 63% yield) compared to that of 3a (entry 1 in Table 1; 18 h, 34% yield). Notably, the stereoselectivity (1:4 vs 1:7) is somewhat different between the two reactions, which may indicate different reaction mechanisms involving different alkylidene intermediates (10 vs 4) from enyne substrates 5a and 3a, respectively. The protecting group change in alkene counterpart from 8a to 8c in the CM reaction with 5a did not significantly change the yield and stereoselectivity, affording acetate 14a in 59% yield with an E/Z ratio of 1:5 (entry 2). The highest yield was obtained from the CM of the TBS-protected enyne 5b with alkene 8c, affording CM product 14b in 80% yield and an E/Z ratio of 1:10 (entry 3). The CM reaction of electron deficient substrate 5c with alkene 8c provided the conjugated ethyl alkynoate 14c in 66% yield with excellent Z-selectivity (entry 4). The significantly different reaction rate between 5b and 5c at the same temperature (0.7 h vs 10 h) implies that the generation of alkylidene species such as 15 becomes slower if the resultant alkylidene is electron deficient. Unexpectedly, the CM of 5d, which does not carry electron-withdrawing (13) A similar strategy to generate alkylidene at a less reactive site by the initiation from the remote site followed by intramolecular delivery of the catalyst has been pursued by Hoye and co-workers and termed “Relay Metathesis”. See: Zhao, H. Ph.D. Thesis, University of Minnesota, 2001. Lange, B. S. Abstracts of Papers, 227th National Meeting of the American Chemical Society, Anaheim, CA; American Chemical Society: Washington, DC, 2004; CHED 899. See also ref 12b and Robinson, J.; Piscopio, A. D. Abstracts of Papers, 226th National Meeting of the American Chemical Society, New York, NY; American Chemical Society: Washington, DC, September, 2003. (14) The involvement of a slow initiating methylidene in the former could also result in inefficient turn over. (15) For the preparation of 5, see the Supporting Information. 2037
Table 2. CM Reaction of Enynes Containing an Allyl Ether Moiety for Catalyst Deliverya
a Typical reaction conditions: Catalyst 6 was added to a solution of the enyne 5 and the alkene 8 or alkyne 13 in CH2Cl2. b Determined by 1H NMR. c Isolated yield.
substituents (entry 5), is similar to that of 5c, providing a 60% yield of 14d in 14 h but with reduced Z-selectivity (1: 20 vs 1:7). We next used enyne 13a,b as the CM partner where the ene moiety is deactivated by steric hindrance of three substituents, leaving the alkyne moiety as the initially reacting functional group with alkylidene 4. The CM reaction between 5e and enyne 13a provided the conjugated dienyne 14e in 55% yield and a 1.5:1 ratio of E/Z isomers (entry 6). A similar result was obtained from the CM with a slightly different enyne 13b, affording 14f in 25% yield with E/Z selectivity favoring the E-isomer in a 3:1 ratio.16 The sudden change in E/Z selectivity in the reaction of 13a and 13b is not clear at this point. The formation of products 14e,f has important mechanistic implication for these CM reactions which supports our mechanistic hypothesis depicted in Scheme 1 because the cross-coupling between 5e and 13a,b is possible only if the reaction occurs via the intermediacy of alkylidene 4. Another salient feature of the CM reaction with enyne 5 is the facile formation of the electron-deficient conjugated alkylidenes 15 and 16 in the presence of normal alkenes. Additionally, the alkene initiation can be deduced from the formation of (16) The formation of cross-coupled products 14e,f is a strong indication of the preferential initiation of the metathesis at the alkene moiety over the alkyne. 2038
14e,f in the CM reaction with the sterically and stereoelectronically unbiased allyl and propargyl group in 5e and 13a,b, which provides an insight into one of the most controversial mechanistic question in enyne metathesis; whether the initiation occurs at the alkene or the alkyne. The favorable involvement of putative alkylidene species 15 and 16 in CM reaction suggests that other electron deficient, thus very reactive,17 conjugated alkylidene species 17 and 18 might also be generated similarly using the catalyst delivery vehicle strategy such as in the reaction of 19 and 21 (Scheme 2). To test the feasibility of this reasoning, 19 and 20 were treated with stoichiometric amount of 6 and the progress was monitored by 1H NMR (Scheme 2, eq 2). The formation of dihydrofuran in both reactions strongly suggests initiation at the terminal alkene followed by catalyst delivery to the R-carbon of the carbonyl group to generate 17 and 18. These electron-deficient alkylidenes were not directly observed by NMR due to rapid catalytic turnover by 17 and 18 to form methyl acrylate and acrolein, respectively.18 However, the CM reaction of 19 in the presence of alkene 8a and catalytic amount of 6 provided only the terminal allyl group cross-coupled product 21, which indicates the formation of enoate alkylidene intermediate 17 is prohibited in the presence of external alkene. Interestingly, the CM reaction of aldehyde 20 afforded 2:1 mixture of 22 and 23 (Scheme 2, eq 4). We believe enal 22 is derived from a propagating alkylidene 18. In summary, we achieved the efficient cross metathesis reaction between conjugated enynes and alkenes by designing a novel substrate containing a catalyst delivery vehicle. By using this device a conjugated alkynyl alkylidene of type 4 could be generated and utilized for CM reaction, which should find useful application in other types of metathesis processes. Further study toward the formation of cyclic and acyclic enediynes using this strategy is underway. Acknowledgment. D.L. gratefully acknowledges the Wisconsin Alumni Research Foundation for research funding and the Camille and Henry Dreyfus Foundation for a New Faculty Award. Supports for NMR and mass spectrometry instrumentation from the NSF and NIH are greatly acknowledged. Note Added after ASAP. Footnote 13 of the version posted ASAP on May 19, 2004 has been corrected; the corrected version was posted May 21, 2004. Supporting Information Available: Experimental details and characterization for new compounds. This material is available free of charge via the Internet at http://pubs.acs.org. OL049378I (17) (a) Ulman, M.; Belderrain, T. R.; Grubbs, R. H. Tetrahedron Lett. 2000, 41, 4689. (b) Choi, T. L.; Lee, C. W.; Chatterjee, A. K.; Grubbs, R. H. J. Am. Chem. Soc. 2001, 123, 10417. (18) Although a stoichiometric amount of catalyst was used, only a small fraction underwent initiation to catalyze the reaction of 19 and 20. Therefore, only a small amount of styrene was observed by NMR. Org. Lett., Vol. 6, No. 12, 2004
